Abstract The primary route for consuming marijuana, the most commonly used recreational drug, is by smoking; yet, its effects on the lung remain largely unexplored. Two cannabinoid receptors (CBR), which bind both to endogenous cannabinoids and to ?9-tetrahydrocannabinol (THC ? the primary active component of marijuana) are described. Although CB1R is classically reported to be expressed in the central nervous system, recent publications and preliminary data in this grant indicate expression in macrophages in the lung. CB2R is also expressed on alveolar macrophages. The effect of CBR signaling in host response to infectious exposures have primarily been limited to studying impact of endogenous cannabinoids via genetic deletion of CBRs and/or use of pharmacologic inhibitors. Published data are inconclusive and support both beneficial and harmful effects of CBR signaling in response to bacterial and viral infections. Furthermore, data on the effects of exogenous cannabinoid signaling via marijuana exposure on host response to infections, including influenza infection are lacking. This project proposes to investigate the impact of marijuana smoke exposure on the lung using clinically relevant animal models and state-of-the-art molecular biology methods. Utilizing a smoking chamber, we will expose normal mice and mice lacking CB1R or CBR2 to marijuana for up to 4 weeks. The impact of marijuana smoke and CBR2 signaling on host response to influenza and macrophage phenotype will be determined in Aim 1. Aim 2 investigates whether marijuana smoke exposure alters resolution of lung injury, promoting fibrosis. Collectively, this project will provide new insights into the role played by marijuana use in altering the lung?s immune state and lay the groundwork for future studies to unravel the potential pathophysiologic consequences of chronic marijuana use. Given that studies also implicate CBR signaling in non-infectious lung diseases such as asthma and pulmonary fibrosis, findings will have potential impact beyond influenza infection.